基于临床选择的基因检测与表型诊断的广泛种系测序在诊断儿童癌症遗传倾向方面的比较:一项前瞻性诊断研究。

IF 19.9 1区 医学 Q1 PEDIATRICS Lancet Child & Adolescent Health Pub Date : 2024-08-16 DOI:10.1016/S2352-4642(24)00144-5
Jette J Bakhuizen MD , Freerk van Dijk MSc , Marco J Koudijs PhD , Reno S Bladergroen BSc , Sebastian B B Bon MD , Saskia M J Hopman PhD , Lennart A Kester PhD , Mariëtte E G Kranendonk PhD , Jan L C Loeffen PhD , Stephanie E Smetsers PhD , Edwin Sonneveld PhD , Melissa Tachdjian BA , Evelien de Vos-Kerkhof PhD , Catherine Goudie MD , Prof Johannes H M Merks PhD , Prof Roland P Kuiper PhD , Marjolijn C J Jongmans PhD
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引用次数: 0

摘要

背景:自从引入肿瘤-种系配对测序以来,种系数据已在儿科肿瘤学中广泛使用。为了指导癌症易感综合征(CPS)诊断的最佳实践,我们旨在评估在所有癌症患儿中,与基于临床选择的基因检测相比,广泛的种系分析的诊断率:在这项前瞻性诊断研究中,所有在 2020 年 6 月 1 日至 2022 年 7 月 31 日期间在荷兰国家中心--马克西马公主儿科肿瘤中心(荷兰乌得勒支)接受治疗的新诊断肿瘤患儿(0-19 岁)都接受了两种方法来识别 CPS。在表型驱动法中,儿科肿瘤学家使用麦吉尔互动式儿科肿瘤遗传指南工具选择患儿转诊给临床遗传学家并进行基因检测。在表型诊断方法中,为所有儿童提供 CPS 基因面板测序(143 个基因)。在拒绝接受 CPS 研究基因小组测序的儿童中,49 个 CPS 基因仍由病理学家作为常规诊断的一部分进行分析。在肿瘤诊断前已发现致病 CPS 的儿童不包括在内。研究的主要目的是比较两种方法诊断出的 CPS 患者的数量和类型:1052名儿童符合本研究的条件,其中733人(70%)完成了表型驱动法和表型诊断法的CPS基因组测序(143个基因 n=600; 49个基因 n=133)。在 53 名儿童中发现了 CPS:14人(26%)仅通过表型驱动法确诊,22人(42%)仅通过CPS基因测序确诊,17人(32%)通过两种方法确诊。在 53 名患儿中,有 27 人(51%)被认为是肿瘤的致病因素。在表型驱动法漏检的27个致病CPS中,只有1个(4%)是仅通过表型不确定的CPS基因测序鉴定出来的。在 26 名(49%)儿童中,发现了一种因果关系不确定的 CPS,其中包括 14 种成人发病的 CPS。因果关系不确定的 CPS 主要是通过表型诊断方法发现的(26 例中有 21 例 [81%]):表型驱动的基因检测和表型诊断的 CPS 基因组测序是互补的。表型驱动法确定了致病性最强的 CPS。CPS 基因组测序确定了更多的 CPSs,其中许多因果关系不确定,但有些具有临床实用性。我们建议对所有肿瘤患儿进行 CPS 临床评估。所有 CPS 基因的表型诊断测试最好只在研究环境中进行,并应与心理咨询相结合:Stichting Kinderen Kankervrij.
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Comparison of clinical selection-based genetic testing with phenotype-agnostic extensive germline sequencing to diagnose genetic predisposition in children with cancer: a prospective diagnostic study

Background

Germline data have become widely available in paediatric oncology since the introduction of paired tumour-germline sequencing. To guide best practice in cancer predisposition syndrome (CPS) diagnostics, we aimed to assess the diagnostic yield of extensive germline analysis compared with clinical selection-based genetic testing among all children with cancer.

Methods

In this prospective diagnostic study, all children (aged 0–19 years) with newly diagnosed neoplasms treated in the Netherlands national centre, the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands), between June 1, 2020, and July 31, 2022, were offered two approaches to identify CPSs. In a phenotype-driven approach, paediatric oncologists used the McGill Interactive Pediatric OncoGenetic Guidelines tool to select children for referral to a clinical geneticist, and for genetic testing. In a phenotype-agnostic approach, CPS gene panel sequencing (143 genes) was offered to all children. In children declining the research CPS gene panel, 49 CPS genes were still analysed as part of routine diagnostics by the pathologist. Children with a causative CPS identified before neoplasm diagnosis were excluded. The primary objective was to compare the number and type of patients diagnosed with a CPS between the two approaches.

Findings

1052 children were eligible for this study, of whom 733 (70%) completed both the phenotype-driven approach and received phenotype-agnostic CPS gene panel sequencing (143 genes n=600; 49 genes n=133). In 53 children, a CPS was identified: 14 (26%) were diagnosed by the phenotype-driven approach only, 22 (42%) by CPS gene sequencing only, and 17 (32%) by both approaches. In 27 (51%) of the 53 children, the identified CPS was considered causative for the child's neoplasm. Only one (4%) of the 27 causative CPSs was missed by the phenotype-driven approach and was identified solely by phenotype-agnostic CPS gene sequencing. In 26 (49%) children, a CPS with uncertain causality was identified, including 14 adult-onset CPSs. The CPSs with uncertain causality were mainly detected by the phenotype-agnostic approach (21 [81%] of 26).

Interpretation

Phenotype-driven genetic testing and phenotype-agnostic CPS gene panel sequencing were complementary. The phenotype-driven approach identified the most causative CPSs. CPS gene panel sequencing identified additional CPSs, many of those with uncertain causality, but some with clinical utility. We advise clinical evaluation for CPSs in all children with neoplasms. Phenotype-agnostic testing of all CPS genes is preferably conducted only in research settings and should be paired with counseling.

Funding

Stichting Kinderen Kankervrij.

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来源期刊
Lancet Child & Adolescent Health
Lancet Child & Adolescent Health Psychology-Developmental and Educational Psychology
CiteScore
40.90
自引率
0.80%
发文量
381
期刊介绍: The Lancet Child & Adolescent Health, an independent journal with a global perspective and strong clinical focus, presents influential original research, authoritative reviews, and insightful opinion pieces to promote the health of children from fetal development through young adulthood. This journal invite submissions that will directly impact clinical practice or child health across the disciplines of general paediatrics, adolescent medicine, or child development, and across all paediatric subspecialties including (but not limited to) allergy and immunology, cardiology, critical care, endocrinology, fetal and neonatal medicine, gastroenterology, haematology, hepatology and nutrition, infectious diseases, neurology, oncology, psychiatry, respiratory medicine, and surgery. Content includes articles, reviews, viewpoints, clinical pictures, comments, and correspondence, along with series and commissions aimed at driving positive change in clinical practice and health policy in child and adolescent health.
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